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Engel MG, Narayan S, Cui MH, Branch CA, Zhang X, Gandy SE, Ehrlich M, Huffman DM. Intranasal long R3 insulin-like growth factor-1 treatment promotes amyloid plaque remodeling in cerebral cortex but fails to preserve cognitive function in male 5XFAD mice. J Alzheimers Dis 2025; 103:113-126. [PMID: 39610283 DOI: 10.1177/13872877241299056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
BACKGROUND Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD). OBJECTIVE Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice. METHODS Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n = 19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive in vitro stimulation studies in BV-2 microglial cells were also performed. RESULTS In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. In vitro, uptake of Aβ1-42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis. CONCLUSIONS LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy per se, they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.
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Affiliation(s)
- Matthew G Engel
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Sushma Narayan
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Min-Hui Cui
- Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Craig A Branch
- Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Xusheng Zhang
- Computational Genomics Core, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Samuel E Gandy
- Department of Neurology and the Mount Sinai Center for Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry and the Mount Sinai Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michelle Ehrlich
- Department of Neurology and the Mount Sinai Center for Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry and the Mount Sinai Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Derek M Huffman
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
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Wang KC, Ojeda NB, Wang H, Chiang HS, Tucci MA, Lee JW, Wei HC, Kaizaki-Mitsumoto A, Tanaka S, Dankhara N, Tien LT, Fan LW. Neonatal brain inflammation enhances methamphetamine-induced reinstated behavioral sensitization in adult rats analyzed with explainable machine learning. Neurochem Int 2024; 176:105743. [PMID: 38641026 PMCID: PMC11102812 DOI: 10.1016/j.neuint.2024.105743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 03/15/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024]
Abstract
Neonatal brain inflammation produced by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) results in long-lasting brain dopaminergic injury and motor disturbances in adult rats. The goal of the present work is to investigate the effect of neonatal systemic LPS exposure (1 or 2 mg/kg, i.p. injection in postnatal day 5, P5, male rats)-induced dopaminergic injury to examine methamphetamine (METH)-induced behavioral sensitization as an indicator of drug addiction. On P70, subjects underwent a treatment schedule of 5 once daily subcutaneous (s.c.) administrations of METH (0.5 mg/kg) (P70-P74) to induce behavioral sensitization. Ninety-six hours following the 5th treatment of METH (P78), the rats received one dose of 0.5 mg/kg METH (s.c.) to reintroduce behavioral sensitization. Hyperlocomotion is a critical index caused by drug abuse, and METH administration has been shown to produce remarkable locomotor-enhancing effects. Therefore, a random forest model was used as the detector to extract the feature interaction patterns among the collected high-dimensional locomotor data. Our approaches identified neonatal systemic LPS exposure dose and METH-treated dates as features significantly associated with METH-induced behavioral sensitization, reinstated behavioral sensitization, and perinatal inflammation in this experimental model of drug addiction. Overall, the analysis suggests that the implementation of machine learning strategies is sensitive enough to detect interaction patterns in locomotor activity. Neonatal LPS exposure also enhanced METH-induced reduction of dopamine transporter expression and [3H]dopamine uptake, reduced mitochondrial complex I activity, and elevated interleukin-1β and cyclooxygenase-2 concentrations in the P78 rat striatum. These results indicate that neonatal systemic LPS exposure produces a persistent dopaminergic lesion leading to a long-lasting change in the brain reward system as indicated by the enhanced METH-induced behavioral sensitization and reinstated behavioral sensitization later in life. These findings indicate that early-life brain inflammation may enhance susceptibility to drug addiction development later in life, which provides new insights for developing potential therapeutic treatments for drug addiction.
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Affiliation(s)
- Kuo-Ching Wang
- Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei City, Taiwan
| | - Norma B Ojeda
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA; Department of Advanced Biomedical Education, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Haifeng Wang
- Department of Industrial and Systems Engineering, Mississippi State University, Mississippi State, MS, 39762, USA
| | - Han-Sun Chiang
- School of Medicine, Fu Jen Catholic University, Xinzhuang Dist, New Taipei City, 24205, Taiwan
| | - Michelle A Tucci
- Department of Anesthesiology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Jonathan W Lee
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Han-Chi Wei
- School of Medicine, Fu Jen Catholic University, Xinzhuang Dist, New Taipei City, 24205, Taiwan
| | - Asuka Kaizaki-Mitsumoto
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA; Department of Toxicology, Showa University Graduate School of Pharmacy, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Sachiko Tanaka
- Center for Research and Development in Pharmacy Education, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Nilesh Dankhara
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Lu-Tai Tien
- School of Medicine, Fu Jen Catholic University, Xinzhuang Dist, New Taipei City, 24205, Taiwan.
| | - Lir-Wan Fan
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
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Zou X, Zhang J, Wang Y, Zhou D, Deng G, Liu Z. IGF-1 rs6218 polymorphisms modulate the susceptibility to age-related cataract. PeerJ 2024; 12:e17220. [PMID: 38618568 PMCID: PMC11011587 DOI: 10.7717/peerj.17220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/20/2024] [Indexed: 04/16/2024] Open
Abstract
Background Single nucleotide polymorphisms (SNPs), as the most abundant form of DNA variation in the human genome, contribute to age-related cataracts (ARC) development. Apoptosis of lens epithelial cells (LECs) is closely related to ARC formation. Insulin-like growth factor 1 (IGF1) contributes to cell apoptosis regulation. Moreover, IGF1 was indicated to exhibit a close association with cataract formation. Afterward, an investigation was conducted to examine the correlation between polymorphisms in IGF1 and the susceptibility to ARC. Methods The present investigation was a case-control study. Venous blood draws were collected from the participants for DNA genotyping. Lens capsule samples were collected to detect mRNA and apoptosis. TaqMan RT-PCR was used to detect IGF1 polymorphism genotypes and qRT PCR was used to detect IGF1 mRNA levels in LECs. LEC apoptosis was evaluated through flow cytometry. The chi-square test was used to compare differences between ARCs and controls of each SNP. Results We found that the G allele frequency in the IGF1-rs6218 was higher in the ARCs than in the controls. Furthermore, it was observed that the rs6218 GG genotype exhibited a positive correlation to elevated levels of IGF1 mRNA in LECs. The IGF1 mRNA in the LECs and the apoptosis of LECs in nuclear type of ARCs (ARNC) was higher than the controls. Conclusion The susceptibility to ARC was related to IGF1-rs6218 polymorphism, and this polymorphism is associated with IGF1 expression at the mRNA level. Moreover, apoptosis in LECs of ARNCs was found to be increased.
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Affiliation(s)
- Xi Zou
- Changzhou Medical Center, Changzhou, China
- The Third People’s Hospital of Changzhou, Changzhou, China
| | - Jun Zhang
- The Third People’s Hospital of Changzhou, Changzhou, China
| | - Yong Wang
- Nantong First People’s Hospital, Nantong, China
| | - Dong Zhou
- The Third People’s Hospital of Changzhou, Changzhou, China
| | - Guohua Deng
- The Third People’s Hospital of Changzhou, Changzhou, China
| | - Zhinan Liu
- The Third People’s Hospital of Changzhou, Changzhou, China
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Talati CP, Lee JW, Lu S, Ojeda NB, Prakash V, Dankhara N, Nielson TC, Sandifer SP, Bidwell GL, Pang Y, Fan LW, Bhatt AJ. Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal apoptosis, and brain damage in neonatal rats. CURRENT RESEARCH IN NEUROBIOLOGY 2023; 6:100123. [PMID: 38235171 PMCID: PMC10793091 DOI: 10.1016/j.crneur.2023.100123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/10/2023] [Accepted: 12/14/2023] [Indexed: 01/19/2024] Open
Abstract
There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 μg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.
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Affiliation(s)
- Chirag P. Talati
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Jonathan W. Lee
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Silu Lu
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Norma B. Ojeda
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Varsha Prakash
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Nilesh Dankhara
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Tanner C. Nielson
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Sara P. Sandifer
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Gene L. Bidwell
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Yi Pang
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Lir-Wan Fan
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Abhay J. Bhatt
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
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Wang S, Hou K, Gui S, Ma Y, Wang S, Zhao S, Zhu X. Insulin-like growth factor 1 in heat stress-induced neuroinflammation: novel perspective about the neuroprotective role of chromium. STRESS BIOLOGY 2023; 3:23. [PMID: 37676529 PMCID: PMC10441889 DOI: 10.1007/s44154-023-00105-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/06/2023] [Indexed: 09/08/2023]
Abstract
Heat stress (HS) can cause a series of stress responses, resulting in numerous negative effects on the body, such as the diminished food intake, carcass quality and reproductive capacity. In addition to the negative effects on the peripheral system, HS leads to central nervous system (CNS) disorders given its toll on neuroinflammation. This neuroinflammatory process is mainly mediated by microglia and astrocytes, which are involved in the activation of glial cells and the secretion of cytokines. While the regulation of inflammatory signaling has a close relationship with the expression of heat shock protein 70 (Hsp70), HS-induced neuroinflammation is closely related to the activation of the TLR4/NF-κB pathway. Moreover, oxidative stress and endoplasmic reticulum (ER) stress are key players in the development of neuroinflammation. Chromium (Cr) has been widely shown to have neuroprotective effects in both humans and animals, despite the lack of mechanistic evidence. Evidence has shown that Cr supplementation can increase the levels of insulin-like growth factor 1 (IGF-1), a major neurotrophic factor with anti-inflammatory and antioxidant effects. This review highlights recent advances in the attenuating effects and potential mechanisms of Cr-mediated IGF-1 actions on HS-induced neuroinflammation, providing presently existing evidence supporting the neuroprotective role of Cr.
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Affiliation(s)
- Songlin Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Kanghui Hou
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Siqi Gui
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Yue Ma
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Shuai Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Shanting Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Xiaoyan Zhu
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China.
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Püspök JF, Zhao S, Calma AD, Vourlitis GL, Allison SD, Aronson EL, Schimel JP, Hanan EJ, Homyak PM. Effects of experimental nitrogen deposition on soil organic carbon storage in Southern California drylands. GLOBAL CHANGE BIOLOGY 2023; 29:1660-1679. [PMID: 36527334 DOI: 10.1111/gcb.16563] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/18/2022] [Indexed: 05/28/2023]
Abstract
Atmospheric nitrogen (N) deposition is enriching soils with N across biomes. Soil N enrichment can increase plant productivity and affect microbial activity, thereby increasing soil organic carbon (SOC), but such responses vary across biomes. Drylands cover ~45% of Earth's land area and store ~33% of global SOC contained in the top 1 m of soil. Nitrogen fertilization could, therefore, disproportionately impact carbon (C) cycling, yet whether dryland SOC storage increases with N remains unclear. To understand how N enrichment may change SOC storage, we separated SOC into plant-derived, particulate organic C (POC), and largely microbially derived, mineral-associated organic C (MAOC) at four N deposition experimental sites in Southern California. Theory suggests that N enrichment increases the efficiency by which microbes build MAOC (C stabilization efficiency) if soil pH stays constant. But if soils acidify, a common response to N enrichment, then microbial biomass and enzymatic organic matter decay may decrease, increasing POC but not MAOC. We found that N enrichment had no effect on C fractions except for a decrease in MAOC at one site. Specifically, despite reported increases in plant biomass in three sites and decreases in microbial biomass and extracellular enzyme activities in two sites that acidified, POC did not increase. Furthermore, microbial C use and stabilization efficiency increased in a non-acidified site, but without increasing MAOC. Instead, MAOC decreased by 16% at one of the sites that acidified, likely because it lost 47% of the exchangeable calcium (Ca) relative to controls. Indeed, MAOC was strongly and positively affected by Ca, which directly and, through its positive effect on microbial biomass, explained 58% of variation in MAOC. Long-term effects of N fertilization on dryland SOC storage appear abiotic in nature, such that drylands where Ca-stabilization of SOC is prevalent and soils acidify, are most at risk for significant C loss.
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Affiliation(s)
- Johann F Püspök
- Department of Environmental Sciences, University of California, Riverside, California, USA
| | - Sharon Zhao
- Department of Environmental Sciences, University of California, Riverside, California, USA
| | - Anthony D Calma
- Department of Environmental Sciences, University of California, Riverside, California, USA
| | - George L Vourlitis
- Department of Biological Sciences, California State University, San Marcos, California, USA
| | - Steven D Allison
- Department of Ecology and Evolutionary Biology, University of California, Irvine, California, USA
- Department of Earth System Science, University of California, Irvine, California, USA
| | - Emma L Aronson
- Department of Microbiology and Plant Pathology, University of California, Riverside, California, USA
| | - Joshua P Schimel
- Department of Ecology, Evolution, and Marine Biology and Earth Research Institute, University of California, Santa Barbara, California, USA
| | - Erin J Hanan
- Department of Natural Resources and Environmental Science, University of Nevada, Reno, Nevada, USA
| | - Peter M Homyak
- Department of Environmental Sciences, University of California, Riverside, California, USA
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Hyperbaric Oxygen Therapy Alleviates Social Behavior Dysfunction and Neuroinflammation in a Mouse Model for Autism Spectrum Disorders. Int J Mol Sci 2022; 23:ijms231911077. [PMID: 36232395 PMCID: PMC9570008 DOI: 10.3390/ijms231911077] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/15/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022] Open
Abstract
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder (NDD) characterized by impaired social communication and repetitive behavior, among other symptoms. ASD is highly heritable, with SHANK3 being one of the high-risk genes for ASD. In recent years, knowledge has been growing regarding the neuroplasticity effect induced by hyperbaric oxygen therapy (HBOT) and its potential use for ASD. Here, we characterized the effect of HBOT on a mouse model for ASD with the human genetic condition of InsG3680 mutation in the Shank3 gene. As compared to placebo, HBOT improved social behavior and reduced neuroinflammation in the cortex of the InsG3680(+/+) mice. Specifically, HBOT induced upregulation of Insulin-like growth factor 1 (Igf1) expression levels and reduced the number of Iba1-positive cells in the mouse model for ASD compared to placebo control. Together, our research suggests that HBOT has the potential to improve the clinical outcome of ASD by ameliorating some of the core pathophysiological processes responsible for the development of the disorder.
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Pierre WC, Zhang E, Londono I, De Leener B, Lesage F, Lodygensky GA. Non-invasive in vivo MRI detects long-term microstructural brain alterations related to learning and memory impairments in a model of inflammation-induced white matter injury. Behav Brain Res 2022; 428:113884. [DOI: 10.1016/j.bbr.2022.113884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/18/2022] [Accepted: 04/03/2022] [Indexed: 11/28/2022]
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Siahanidou T, Spiliopoulou C. Pharmacological Neuroprotection of the Preterm Brain: Current Evidence and Perspectives. Am J Perinatol 2022; 39:479-491. [PMID: 32961562 DOI: 10.1055/s-0040-1716710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Despite improvements in viability, the long-term neurodevelopmental outcomes of preterm babies remain serious concern as a significant percentage of these infants develop neurological and/or intellectual impairment, and they are also at increased risk of psychiatric illnesses later in life. The current challenge is to develop neuroprotective approaches to improve adverse outcomes in preterm survivors. The purpose of this review was to provide an overview of the current evidence on pharmacological agents targeting the neuroprotection of the preterm brain. Among them, magnesium sulfate, given antenatally to pregnant women with imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine administered to preterm infants after birth, exhibited neuroprotective effects for human preterm brain. Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions. Further studies are also required to assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be implemented as neuroprotectants in clinical practice. Furthermore, other pharmacological agents showing promising signs of neuroprotective efficacy in preclinical studies (growth factors, hyaluronidase inhibitors or treatment, antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as well as stem cell- or exosomal-based therapies and nanomedicine, may prove useful in the future as potential neuroprotective approaches for human preterm brain. KEY POINTS: · Magnesium and caffeine have neuroprotective effects for the preterm brain.. · Follow-up of infants treated with erythropoietin is needed.. · Neuroprotective efficacy of several drugs in animals needs to be shown in humans..
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Affiliation(s)
- Tania Siahanidou
- Neonatal Unit of the First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Wu L, Qin Y, Yuan H, Zhu Y, Hu A. Anti-inflammatory and neuroprotective effects of insulin-like growth factor-1 overexpression in pentylenetetrazole (PTZ)-induced mouse model of chronic epilepsy. Brain Res 2022; 1785:147881. [DOI: 10.1016/j.brainres.2022.147881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 01/11/2022] [Accepted: 03/08/2022] [Indexed: 11/28/2022]
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Shinjyo N, Kita K. Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia. Front Cell Neurosci 2021; 15:765217. [PMID: 34795562 PMCID: PMC8592913 DOI: 10.3389/fncel.2021.765217] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer's disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.
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Affiliation(s)
- Noriko Shinjyo
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.,Laboratory of Immune Homeostasis, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Kiyoshi Kita
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.,Department of Host-Defense Biochemistry, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
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Mehmood Siddiqui E, Mehan S, Upadhayay S, Khan A, Halawi M, Ahmed Halawi A, Alsaffar RM. Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage. Saudi J Biol Sci 2021; 28:6417-6431. [PMID: 34764759 PMCID: PMC8568986 DOI: 10.1016/j.sjbs.2021.07.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/15/2021] [Accepted: 07/04/2021] [Indexed: 02/08/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a severe form of brain injury, which is a major cause of mortality in humans. Hydrocephalus and cerebral hematoma lead to severe neurological deficits. A single autologous blood (ALB) injection in rats' brains induces hemorrhage and other conditions that regularly interfere with the standard treatment of several cellular and molecular pathways. Several studies have found that IGF-1/GLP-1 decreases the production of inflammatory markers in peripheral tissues, while some have found that they also have pro-inflammatory functions. Since these receptors are down-regulated in hemorrhagic situations, we looked into the potential neuroprotective effect of 4-hydroxyisoleucine (4-HI); 50 mg/kg and 100 mg/kg, an active compound Trigonellafoenum-graecum, on post-hemorrhagic deficits in rats. Long-term oral administration of 4-HI for 35 days has improved behavioral and neurochemical deficits and severe pathological changes and improved cellular and molecular markers, apoptotic markers in the ALB-induced ICH experimental model. Furthermore, the findings revealed that 4-HI also improved the levels of other neurotransmitters (Ach, DOPA, GABA, glutamate); inflammatory cytokines (TNF-alpha, IL-1β, IL-17), and oxidative stress markers (MDA, nitrite, LDH, AchE, SOD, CAT, GPx, GSH) in the brain when evaluated after Day 35. There is no proven treatment available for the prevention of post-brain hemorrhage and neurochemical malfunction; available therapy is only for symptomatic relief of the patient. Thus, 4-HI could be a potential clinical approach for treating post-brain haemorrhage and neurochemical changes caused by neurological damage. Furthermore, 4-HI may be linked to other standard therapeutic therapies utilized in ICH as a potential pharmacological intervention.
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Affiliation(s)
- Ehraz Mehmood Siddiqui
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Shubham Upadhayay
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Maryam Halawi
- Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | | | - Rana M Alsaffar
- Department of Pharmacology & Toxicology, College of Pharmacy Girls Section, Prince Sattam Bin Abdulaziz University, P.O.Box-173, Al-Kharj 11942, Saudi Arabia
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13
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Cote DJ, Creed JH, Samanic CM, Gerke TA, Stampfer MJ, Smith-Warner SA, Egan KM. A prospective study of inflammatory biomarkers and growth factors and risk of glioma in the UK Biobank. Cancer Epidemiol 2021; 75:102043. [PMID: 34564026 DOI: 10.1016/j.canep.2021.102043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/08/2021] [Accepted: 09/14/2021] [Indexed: 11/27/2022]
Abstract
PURPOSE The role of growth factors and inflammation in the onset of glioma is poorly understood, and conflicting reports of associations of circulating IGF-1 and inflammatory biomarkers with glioma risk exist in the literature. We examined associations between C-reactive protein (CRP), white blood cell count (WBC), neutrophil-to-lymphocyte ratio (NLR), and insulin-like growth factor-1 (IGF-1) and glioma risk in the UK Biobank cohort. METHODS Hazard ratios (HR) and 95% confidence intervals (CI) for glioma according to circulating biomarkers concentrations were calculated using Cox proportional hazards regression, adjusted for age, sex, race, and education. Analyses were conducted separately for glioma overall and by glioma subtype. RESULTS We identified 417 incident glioma cases among 428,537 participants with 3,255,815 person-years of follow up. Weak, non-significant associations were observed with increasing levels of these biomarkers for risk of glioma overall or by glioma subtype. Among women only, IGF-1 in the highest quartile was positively associated with glioma risk compared to the lowest quartile (HR=1.64, 95%CI: 1.03-2.60, p-trend=0.08), as was NLR (HR=1.54, 95%CI: 1.00-2.39, p-trend=0.05). CONCLUSION In this prospective cohort, we found no significant associations between the inflammatory biomarkers CRP and WBC and the development of glioma. NLR and IGF-1 were associated with risk in women, but not men. When considered with previous studies, further investigation of NLR and IGF-1 as markers of glioma risk appears warranted, particularly in women.
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Affiliation(s)
- David J Cote
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, United States; Computational Neuroscience Outcomes Center, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, United States.
| | - Jordan H Creed
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
| | - Claudine M Samanic
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Travis A Gerke
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Meir J Stampfer
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Stephanie A Smith-Warner
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Kathleen M Egan
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
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Kim DJ, Cho SY, Kim SU, Jo DW, Hwang HI, Shin HK, Jun YH. IGF-1 Protects Neurons in the Cortex and Subventricular Zone in a Periventricular Leucomalacia Model. In Vivo 2021; 35:307-312. [PMID: 33402478 DOI: 10.21873/invivo.12260] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM Chronic cerebral hypoperfusion affects early and mature neurons in the subventricular zone (SVZ) and cerebral cortex. Herein, we investigated the effects of insulin-like growth factor-1 (IGF-1), a neurogenesis-promoting agent, on neurons in these regions in periventricular leucomalacia (PVL) model rats. MATERIALS AND METHODS Following right carotid artery ligation, the rats were placed in a hypoxia chamber and injected with recombinant IGF-1 (0.1 and 1 μg/μl). Their brain sections were immunohistochemically analysed using anti-nestin and anti-NeuN antibodies. RESULTS The numbers of early-neuronal cells in the SVZ and mature neurons in the cerebral cortex were higher and lower, respectively, in the PVL group than in the control group. The number of NeuN-positive cells was significantly higher in the IGF-treated group than in the PVL group. CONCLUSION PVL increased the number of early neuronal cells in the SVZ, reducing the survival of mature neurons in the cerebral cortex; IGF-1 reversed these effects.
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Affiliation(s)
- Dong-Joon Kim
- Department of Anaesthesiology and Pain medicine, Chosun University Hospital, Gwang-ju, Republic of Korea
| | - Su-Yeon Cho
- Department of Anaesthesiology and Pain medicine, Chosun University Hospital, Gwang-ju, Republic of Korea
| | - Seung-Un Kim
- Department of Anaesthesiology and Pain medicine, Chosun University Hospital, Gwang-ju, Republic of Korea
| | - Dong-Won Jo
- Graduate School of Medicine, Chosun University, Gwang-ju, Republic of Korea
| | - Hyo-In Hwang
- Department of Anatomy, School of Medicine, Chosun University, Gwang-ju, Republic of Korea
| | - Hye-Kyoung Shin
- Department of Anatomy, School of Medicine, Chosun University, Gwang-ju, Republic of Korea
| | - Yong-Hyun Jun
- Department of Anatomy, School of Medicine, Chosun University, Gwang-ju, Republic of Korea
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15
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Yeh JH, Wang KC, Kaizaki A, Lee JW, Wei HC, Tucci MA, Ojeda NB, Fan LW, Tien LT. Pioglitazone Ameliorates Lipopolysaccharide-Induced Behavioral Impairment, Brain Inflammation, White Matter Injury and Mitochondrial Dysfunction in Neonatal Rats. Int J Mol Sci 2021; 22:6306. [PMID: 34208374 PMCID: PMC8231261 DOI: 10.3390/ijms22126306] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/29/2021] [Accepted: 06/05/2021] [Indexed: 01/04/2023] Open
Abstract
Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague-Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1β (IL-1β) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1β levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1β induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity.
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Affiliation(s)
- Jiann-Horng Yeh
- Department of Neurobiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan;
- School of Medicine, Fu Jen Catholic University, Xinzhuang Dist., New Taipei City 24205, Taiwan; (K.-C.W.); (H.-C.W.)
| | - Kuo-Ching Wang
- School of Medicine, Fu Jen Catholic University, Xinzhuang Dist., New Taipei City 24205, Taiwan; (K.-C.W.); (H.-C.W.)
- Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
| | - Asuka Kaizaki
- Department of Pharmacology, Toxicology and Therapeutics, Division of Toxicology, School of Pharmacy, Showa University, Shingawa-ku, Tokyo 142-8555, Japan;
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; (J.W.L.); (N.B.O.); (L.-W.F.)
| | - Jonathan W. Lee
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; (J.W.L.); (N.B.O.); (L.-W.F.)
| | - Han-Chi Wei
- School of Medicine, Fu Jen Catholic University, Xinzhuang Dist., New Taipei City 24205, Taiwan; (K.-C.W.); (H.-C.W.)
| | - Michelle A. Tucci
- Department of Anesthesiology, University of Mississippi Medical Center, Jackson, MS 39216, USA;
| | - Norma B. Ojeda
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; (J.W.L.); (N.B.O.); (L.-W.F.)
| | - Lir-Wan Fan
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; (J.W.L.); (N.B.O.); (L.-W.F.)
| | - Lu-Tai Tien
- School of Medicine, Fu Jen Catholic University, Xinzhuang Dist., New Taipei City 24205, Taiwan; (K.-C.W.); (H.-C.W.)
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16
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Rhea EM, Logsdon AF, Banks WA, Erickson ME. Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation. Pharmaceutics 2020; 12:pharmaceutics12111120. [PMID: 33233734 PMCID: PMC7699866 DOI: 10.3390/pharmaceutics12111120] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 02/02/2023] Open
Abstract
This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, and traumatic brain injury.
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Affiliation(s)
- Elizabeth M. Rhea
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; (A.F.L.); (W.A.B.); (M.E.E.)
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
- Correspondence: ; Tel.: +1-206-764-2938
| | - Aric F. Logsdon
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; (A.F.L.); (W.A.B.); (M.E.E.)
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - William A. Banks
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; (A.F.L.); (W.A.B.); (M.E.E.)
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Michelle E. Erickson
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; (A.F.L.); (W.A.B.); (M.E.E.)
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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Ross-Munro E, Kwa F, Kreiner J, Khore M, Miller SL, Tolcos M, Fleiss B, Walker DW. Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury. Front Neurol 2020; 11:568814. [PMID: 33193008 PMCID: PMC7642484 DOI: 10.3389/fneur.2020.568814] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 09/18/2020] [Indexed: 12/21/2022] Open
Abstract
Midkine (MK) is a small secreted heparin-binding protein highly expressed during embryonic/fetal development which, through interactions with multiple cell surface receptors promotes growth through effects on cell proliferation, migration, and differentiation. MK is upregulated in the adult central nervous system (CNS) after multiple types of experimental injury and has neuroprotective and neuroregenerative properties. The potential for MK as a therapy for developmental brain injury is largely unknown. This review discusses what is known of MK's expression and actions in the developing brain, areas for future research, and the potential for using MK as a therapeutic agent to ameliorate the effects of brain damage caused by insults such as birth-related hypoxia and inflammation.
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Affiliation(s)
- Emily Ross-Munro
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia
| | - Faith Kwa
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia.,School of Health Sciences, Swinburne University of Technology, Melbourne, VIC, Australia
| | - Jenny Kreiner
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia
| | - Madhavi Khore
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia
| | - Suzanne L Miller
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia
| | - Mary Tolcos
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia
| | - Bobbi Fleiss
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia.,Neurodiderot, Inserm U1141, Universita de Paris, Paris, France
| | - David W Walker
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia
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Adamis D, Coada I, Eikelenboom P, Chu CS, Finn K, Melvin V, Williams J, Meagher DJ, McCarthy G. Delirium, insulin-like growth factor I, growth hormone in older inpatients. World J Psychiatry 2020; 10:212-222. [PMID: 33014722 PMCID: PMC7515747 DOI: 10.5498/wjp.v10.i9.212] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/16/2020] [Accepted: 08/25/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Delirium is a common disorder in elderly medical inpatients with serious adverse outcomes and is characterized by sudden onset, disturbance in attention, awareness, consciousness and cognition, and often with behavioural disturbances. Central to understanding delirium, is understanding mechanisms by which body and brain wellbeing are linked and in particular how brain responses to bodily homeostatic stress is mediated. A number of studies have investigated the relationship between insulin-like growth factor I (IGF-I) and delirium in medically ill hospitalised patients with conflicting results. However, none have investigated growth hormone (GH) which is related to IGF-I via negative feedback.
AIM To investigate the relationship between serum levels of IGF-I and GH, and the occurrence of delirium.
METHODS Prospective, longitudinal, observational study. Consecutive elderly inpatients (aged 70+), were assessed twice weekly with Montreal cognitive assessment (MoCA), Confusion assessment method (CAM), Acute Physiology and Chronic Health Evaluation II. Delirium was defined using CAM. Previous history of dementia was evaluated with the Informant Questionnaire on Cognitive Decline in the Elderly. IGF-I and GH levels were estimated with the ELISA method. Generalized estimating equations (GEE) model was applied for the first five assessments to analyze those longitudinal data.
RESULTS The sample consisted of 198 participants (mean age 80.63 ± 6.81; range 70-97). Of these 92 (46.5%) were females. Eighty six (43.4%) were identified with a history of dementia. Incident or prevalent delirium during hospitalisation was identified with CAM in 40 participants (20.2%). Evaluation of missing values with Little's MCAR test indicated that they were missing completely at random (MCAR χ2 = 12.24, u: 9, P = 0.20). Using GEE for the analysis we found that low MoCA scores, low levels of IGF-I and high levels of GH were significantly associated with any delirium (prevalence, incident, or fluctuating , during the study period (Wald χ2 = 12.231; u: 1, P < 0.001, Wald χ2 = 7.196, u: 1, P = 0.007, Wald χ2 = 6.210; : u: 1, P = 0.013 respectively).
CONCLUSION The results show that low levels of IGF-I, high levels of GH and low scores in cognition are independently associated with the occurrence of any delirium during the hospitalisation of medically ill older people. The results of the study supports the hypothesis that deficits in the immunoreactivity of the brain (low cerebral reserve) may be associated with delirium.
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Affiliation(s)
- Dimitrios Adamis
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
- Department of Psychiatry, Research and Academic Institute of Athens, Athens 11742, Greece
- Department of Psychiatry, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Iulian Coada
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
| | - Piet Eikelenboom
- Department of Psychiatry, GGZinGeest and VuMC, Amsterdam 1081 HV, the Netherlands
| | - Che-Sheng Chu
- Department of Psychiatry and Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Karen Finn
- Department of Biopharmaceutical and Medical Science, School of Science and Computing, Galway-Mayo Institute of Technology, Galway H91 T8NW, Ireland
| | - Vincent Melvin
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
| | - John Williams
- Department of Pathology, Sligo University Hospital, Sligo F91 H684, Ireland
| | - David James Meagher
- Department of Psychiatry, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Geraldine McCarthy
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
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19
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Sénécal V, Barat C, Tremblay MJ. The delicate balance between neurotoxicity and neuroprotection in the context of HIV-1 infection. Glia 2020; 69:255-280. [PMID: 32910482 DOI: 10.1002/glia.23904] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 08/15/2020] [Accepted: 08/16/2020] [Indexed: 12/17/2022]
Abstract
Human immunodeficiency virus type-1 (HIV-1) causes a spectrum of neurological impairments, termed HIV-associated neurocognitive disorder (HAND), following the infiltration of infected cells into the brain. Even though the implementation of antiretroviral therapy reduced the systemic viral load, the prevalence of HAND remains unchanged and infected patients develop persisting neurological disturbances affecting their quality of life. As a result, HAND have gained importance in basic and clinical researches, warranting the need of developing new adjunctive treatments. Nonetheless, a better understanding of the molecular and cellular mechanisms remains necessary. Several studies consolidated their efforts into elucidating the neurotoxic signaling leading to HAND including the deleterious actions of HIV-1 viral proteins and inflammatory mediators. However, the scope of these studies is not sufficient to address all the complexity related to HAND development. Fewer studies focused on an altered neuroprotective capacity of the brain to respond to HIV-1 infection. Neurotrophic factors are endogenous polyproteins involved in neuronal survival, synaptic plasticity, and neurogenesis. Any defects in the processing or production of these crucial factors might compose a risk factor rendering the brain more vulnerable to neuronal damages. Due to their essential roles, they have been investigated for their diverse interplays with HIV-1 infection. In this review, we present a complete description of the neurotrophic factors involved in HAND. We discuss emerging concepts for their therapeutic applications and summarize the complex mechanisms that down-regulate their production in favor of a neurotoxic environment. For certain factors, we finally address opposing roles that rather lead to increased inflammation.
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Affiliation(s)
- Vincent Sénécal
- Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Québec, Quebec, Canada
| | - Corinne Barat
- Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Québec, Quebec, Canada
| | - Michel J Tremblay
- Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Québec, Quebec, Canada.,Département de Microbiologie-infectiologie et immunologie, Faculté de Médecine, Université Laval, Québec, Quebec, Canada
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20
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Janowska J, Gargas J, Ziemka-Nalecz M, Zalewska T, Sypecka J. Oligodendrocyte Response to Pathophysiological Conditions Triggered by Episode of Perinatal Hypoxia-Ischemia: Role of IGF-1 Secretion by Glial Cells. Mol Neurobiol 2020; 57:4250-4268. [PMID: 32691304 PMCID: PMC7467917 DOI: 10.1007/s12035-020-02015-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022]
Abstract
Differentiation of oligodendrocyte progenitors towards myelinating cells is influenced by a plethora of exogenous instructive signals. Insulin-like growth factor 1 (IGF-1) is one of the major factors regulating cell survival, proliferation, and maturation. Recently, there is an ever growing recognition concerning the role of autocrine/paracrine IGF-1 signaling in brain development and metabolism. Since oligodendrocyte functioning is altered after the neonatal hypoxic-ischemic (HI) insult, a question arises if the injury exerts any influence on the IGF-1 secreted by neural cells and how possibly the change in IGF-1 concentration affects oligodendrocyte growth. To quantify the secretory activity of neonatal glial cells, the step-wise approach by sequentially using the in vivo, ex vivo, and in vitro models of perinatal asphyxia was applied. A comparison of the results of in vivo and ex vivo studies allowed evaluating the role of autocrine/paracrine IGF-1 signaling. Accordingly, astroglia were indicated to be the main local source of IGF-1 in the developing brain, and the factor secretion was shown to be significantly upregulated during the first 24 h after the hypoxic-ischemic insult. And conversely, the IGF-1 amounts released by oligodendrocytes and microglia significantly decreased. A morphometric examination of oligodendrocyte differentiation by means of the Sholl analysis showed that the treatment with low IGF-1 doses markedly improved the branching of oligodendroglial cell processes and, in this way, promoted their differentiation. The changes in the IGF-1 amounts in the nervous tissue after HI might contribute to the resulting white matter disorders, observed in newborn children who experienced perinatal asphyxia. Pharmacological modulation of IGF-1 secretion by neural cells could be reasonable solution in studies aimed at searching for therapies alleviating the consequences of perinatal asphyxia.
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Affiliation(s)
- Justyna Janowska
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5, A. Pawinskiego Str., 02-106, Warsaw, Poland
| | - Justyna Gargas
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5, A. Pawinskiego Str., 02-106, Warsaw, Poland
| | - Malgorzata Ziemka-Nalecz
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5, A. Pawinskiego Str., 02-106, Warsaw, Poland
| | - Teresa Zalewska
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5, A. Pawinskiego Str., 02-106, Warsaw, Poland
| | - Joanna Sypecka
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5, A. Pawinskiego Str., 02-106, Warsaw, Poland.
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21
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Ahluwalia A, Jones MK, Hoa N, Tarnawski AS. Mitochondria in gastric epithelial cells are the key targets for NSAIDs-induced injury and NGF cytoprotection. J Cell Biochem 2019; 120:11651-11659. [PMID: 30790334 DOI: 10.1002/jcb.28445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 02/05/2023]
Abstract
Gastric epithelial cells are important components of mucosal protection and targets of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced injury. Diclofenac (DFN) is one of the most widely used NSAIDs; however, even its short-term use can induce gastric erosions and ulcers. Nerve growth factor (NGF) has been reported to act not only on neuronal cells but also on endothelial cells; however, its action on gastric epithelial cells is unknown. This study was aimed to determine, whether NGF can protect gastric epithelial cells against DFN-induced injury, and to determine the underlying molecular mechanisms with a focus on mitochondria, survivin, and insulin-like growth factor 1 (IGF-1). Cultured normal rat gastric mucosal epithelial cells 1 (RGM1) were treated with phosphate-buffered saline (PBS; control), NGF (100 ng/mL) and/or DFN (0.25-1.00 mM) for 4 hours. We examined: (1) cell injury by confocal microscopy; (2) cell death/survival using Calcein AM live cell tracking dye; (3) mitochondrial structure and membrane potential function using MitoTracker in live cells; and (4) expression of NGF, its receptor - tropomyosin receptor kinase A (TrkA), survivin and IGF-1 by immunostaining. DFN treatment of RGM1 cells for 4 hours caused extensive cell injury, mitochondrial disintegration, reduced cell viability (from 94 ± 3% in controls to 14 ± 4% in 0.5 mM DFN-treated cells; P < 0.001), and expression of survivin and IGF-1. NGF treatment significantly increased survivin and IGF-1 expression by 41% and 75%, respectively versus PBS controls. Pretreatment with NGF before DFN treatment reduced mitochondrial damage and cell death by 73% and 82%, respectively versus treatment with DFN alone (all P < 0.001). This study also showed the presence of high-affinity TrkA receptors in the plasma membrane and mitochondria of RGM1 cells indicating novel actions of NGF.
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Affiliation(s)
- Amrita Ahluwalia
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Michael K Jones
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
| | - Neil Hoa
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Andrzej S Tarnawski
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
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22
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Wang R, Yang Y, Xiao M, Guo B, Liu W, Wang H. Neonatal Inhibition of Connexin 36 Ameliorates Fetal Brain Injury Induced by Maternal Noninfectious Fever in Mice. Dev Neurosci 2019; 41:94-101. [PMID: 31112950 DOI: 10.1159/000499735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/19/2019] [Indexed: 11/19/2022] Open
Abstract
Prenatal fever could result in brain function impairments in the offspring. The present study investigated the effect of interleukin-6 (IL-6)-induced maternal fever on the offspring and the involvement of connexin 36 in this process. Pregnant C57BL/6J mice were injected with IL-6 on gestational day 15. The levels of iNOS and COX-2 were measured as an index of neuroinflammation in the brain of newborn pups. Offspring were treated with the connexin 36 (Cx36) inhibitor mefloquine at postnatal day (P)1-P3 or at P40-P42. Rotarod, grip traction, and foot fault tests were carried out to evaluate the motor behavior of adult offspring. Injection of IL-6 led to an elevation of the core temperature in the pregnant dams. Offspring of these dams showed significantly increased COX-2 and iNOS mRNA expression and protein levels in the whole-brain samples and significantly increased Cx36 in the cerebellum. Moreover, offspring of these dams showed motor deficits at an adult age. Neonatal administration of the Cx36 inhibitor mefloquine could prevent these motor deficits. Maternal fever during pregnancy induced by IL-6 injection could lead to neuroinflammation and motor deficits in the offspring. Neonatal inhibition of Cx36 could ameliorate the motor deficits in the offspring, indicating an involvement of Cx36 in the IL-6-induced maternal fever.
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Affiliation(s)
- Ruifen Wang
- Cangzhou Central Hospital of Hebei Province, Cangzhou, China,
| | - Yueqing Yang
- Cangzhou Central Hospital of Hebei Province, Cangzhou, China
| | - Min Xiao
- Cangzhou Central Hospital of Hebei Province, Cangzhou, China
| | - Binfang Guo
- Cangzhou Central Hospital of Hebei Province, Cangzhou, China
| | - Weili Liu
- Cangzhou Central Hospital of Hebei Province, Cangzhou, China
| | - Haiyan Wang
- Cangzhou Central Hospital of Hebei Province, Cangzhou, China
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23
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Wu X, Liu C, Chen L, Du YF, Hu M, Reed MN, Long Y, Suppiramaniam V, Hong H, Tang SS. Protective effects of tauroursodeoxycholic acid on lipopolysaccharide-induced cognitive impairment and neurotoxicity in mice. Int Immunopharmacol 2019; 72:166-175. [PMID: 30986644 DOI: 10.1016/j.intimp.2019.03.065] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/18/2019] [Accepted: 03/31/2019] [Indexed: 01/04/2023]
Abstract
Accumulating evidence has shown that tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of neurological diseases. However, whether TGR5 agonist TUDCA can improve lipopolysaccharide (LPS)-induced cognitive impairment in mice is less clear. Using a model of cognitive impairment with LPS (2.0 μg) we investigated the effects of TUDCA (200 or 400 μg) on cognitive dysfunction and neurotoxicity in mice. Both Morris water maze and Y-maze avoidance tests showed that TUDCA treatment significantly alleviated LPS-induced behavioral impairments. More importantly, we found that TUDCA treatment reversed TGR5 down-regulation, prevented neuroinflammation via inhibiting NF-κB signaling in the hippocampus of LPS-treated mice. Additionally, TUDCA treatment decreased LPS-induced apoptosis through decreasing TUNEL-positive cells and the overexpression of caspase-3, increasing the ratio of Bcl-2/Bax. TUDCA treatment also ameliorated synaptic plasticity impairments by increasing the ratio of mBDNF/proBDNF, the number of dendritic spines and the expression of synapse-associated proteins in the hippocampus. Our results indicated that TUDCA can improve cognitive impairment and neurotoxicity induced by LPS in mice, which is involved in TGR5-mediated NF-κB signaling.
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Affiliation(s)
- Xian Wu
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Caihong Liu
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Liang Chen
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Yi-Feng Du
- Department of Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL, USA
| | - Mei Hu
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Miranda N Reed
- Department of Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL, USA
| | - Yan Long
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Vishnu Suppiramaniam
- Department of Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL, USA
| | - Hao Hong
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China.
| | - Su-Su Tang
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China.
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24
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Baud O, Berkane N. Hormonal Changes Associated With Intra-Uterine Growth Restriction: Impact on the Developing Brain and Future Neurodevelopment. Front Endocrinol (Lausanne) 2019; 10:179. [PMID: 30972026 PMCID: PMC6443724 DOI: 10.3389/fendo.2019.00179] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 03/04/2019] [Indexed: 12/14/2022] Open
Abstract
The environment in which a fetus develops is not only important for its growth and maturation but also for its long-term postnatal health and neurodevelopment. Several hormones including glucocorticosteroids, estrogens and progesterone, insulin growth factor and thyroid hormones, carefully regulate the growth of the fetus and its metabolism during pregnancy by controlling the supply of nutrients crossing the placenta. In addition to fetal synthesis, hormones regulating fetal growth are also expressed and regulated in the placenta, and they play a key role in the vulnerability of the developing brain and its maturation. This review summarizes the current understanding and evidence regarding the involvement of hormonal dysregulation associated with intra-uterine growth restriction and its consequences on brain development.
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Affiliation(s)
- Olivier Baud
- Division of Neonatology and Pediatric Intensive Care, Department of Women-Children-Teenagers, University Hospitals Geneva, Geneva, Switzerland
- Inserm U1141, Sorbonne, Paris Diderot University, Paris, France
- *Correspondence: Olivier Baud
| | - Nadia Berkane
- Division of Obstetrics and Gynecology, Department of Women-Children-Teenagers, University Hospitals Geneva, Geneva, Switzerland
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25
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Lipponen A, El-Osta A, Kaspi A, Ziemann M, Khurana I, KN H, Navarro-Ferrandis V, Puhakka N, Paananen J, Pitkänen A. Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury. Acta Neuropathol Commun 2018; 6:17. [PMID: 29482641 PMCID: PMC5828078 DOI: 10.1186/s40478-018-0519-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 02/15/2018] [Indexed: 11/10/2022] Open
Abstract
Traumatic brain injury (TBI) induces a wide variety of cellular and molecular changes that can continue for days to weeks to months, leading to functional impairments. Currently, there are no pharmacotherapies in clinical use that favorably modify the post-TBI outcome, due in part to limited understanding of the mechanisms of TBI-induced pathologies. Our system biology analysis tested the hypothesis that chronic transcriptomics changes induced by TBI are controlled by altered DNA-methylation in gene promoter areas or by transcription factors. We performed genome-wide methyl binding domain (MBD)-sequencing (seq) and RNA-seq in perilesional, thalamic, and hippocampal tissue sampled at 3 months after TBI induced by lateral fluid percussion in adult male Sprague-Dawley rats. We investigated the regulated molecular networks and mechanisms underlying the chronic regulation, particularly DNA methylation and transcription factors. Finally, we identified compounds that modulate the transcriptomics changes and could be repurposed to improve recovery. Unexpectedly, DNA methylation was not a major regulator of chronic post-TBI transcriptomics changes. On the other hand, the transcription factors Cebpd, Pax6, Spi1, and Tp73 were upregulated at 3 months after TBI (False discovery rate < 0.05), which was validated using digital droplet polymerase chain reaction. Transcription regulatory network analysis revealed that these transcription factors regulate apoptosis, inflammation, and microglia, which are well-known contributors to secondary damage after TBI. Library of Integrated Network-based Cellular Signatures (LINCS) analysis identified 118 pharmacotherapies that regulate the expression of Cebpd, Pax6, Spi1, and Tp73. Of these, the antidepressant and/or antipsychotic compounds trimipramine, rolipramine, fluspirilene, and chlorpromazine, as well as the anti-cancer therapies pimasertib, tamoxifen, and vorinostat were strong regulators of the identified transcription factors, suggesting their potential to modulate the regulated transcriptomics networks to improve post-TBI recovery.
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Affiliation(s)
- Anssi Lipponen
- Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland
| | - Assam El-Osta
- Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC Australia
- Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR
| | - Antony Kaspi
- Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC Australia
| | - Mark Ziemann
- Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC Australia
| | - Ishant Khurana
- Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC Australia
| | - Harikrishnan KN
- Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC Australia
| | - Vicente Navarro-Ferrandis
- Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland
| | - Noora Puhakka
- Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland
| | - Jussi Paananen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
- University of Eastern Finland Bioinformatics Center, University of Eastern Finland, Kuopio, Finland
| | - Asla Pitkänen
- Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland
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26
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Labandeira-Garcia JL, Costa-Besada MA, Labandeira CM, Villar-Cheda B, Rodríguez-Perez AI. Insulin-Like Growth Factor-1 and Neuroinflammation. Front Aging Neurosci 2017; 9:365. [PMID: 29163145 PMCID: PMC5675852 DOI: 10.3389/fnagi.2017.00365] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 10/23/2017] [Indexed: 12/15/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) effects on aging and neurodegeneration is still controversial. However, it is widely admitted that IGF-1 is involved in the neuroinflammatory response. In peripheral tissues, several studies showed that IGF-1 inhibited the expression of inflammatory markers, although other studies concluded that IGF-1 has proinflammatory functions. Furthermore, proinflammatory cytokines such as TNF-α impaired IGF-1 signaling. In the brain, there are controversial results on effects of IGF-1 in neuroinflammation. In addition to direct protective effects on neurons, several studies revealed anti-inflammatory effects of IGF-1 acting on astrocytes and microglia, and that IGF-1 may also inhibit blood brain barrier permeability. Altogether suggests that the aging-related decrease in IGF-1 levels may contribute to the aging-related pro-inflammatory state. IGF-1 inhibits the astrocytic response to inflammatory stimuli, and modulates microglial phenotype (IGF-1 promotes the microglial M2 and inhibits of M1 phenotype). Furthermore, IGF-1 is mitogenic for microglia. IGF-1 and estrogen interact to modulate the neuroinflammatory response and microglial and astrocytic phenotypes. Brain renin-angiotensin and IGF-1 systems also interact to modulate neuroinflammation. Induction of microglial IGF-1 by angiotensin, and possibly by other pro-inflammatory inducers, plays a major role in the repression of the M1 microglial neurotoxic phenotype and the enhancement of the transition to an M2 microglial repair/regenerative phenotype. This mechanism is impaired in aged brains. Aging-related decrease in IGF-1 may contribute to the loss of capacity of microglia to undergo M2 activation. Fine tuning of IGF-1 levels may be critical for regulating the neuroinflammatory response, and IGF-1 may be involved in inflammation in a context-dependent mode.
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Affiliation(s)
- Jose L Labandeira-Garcia
- Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Maria A Costa-Besada
- Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Carmen M Labandeira
- Department of Clinical Neurology, Hospital Alvaro Cunqueiro, University Hospital Complex, Vigo, Spain
| | - Begoña Villar-Cheda
- Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ana I Rodríguez-Perez
- Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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